Over the past year we have began a shift in our focus, moving this project from an ethological Type 2 phenotype assessment to one directly measuring alcohol intake. In our free-ranging population at Morgan Island, 14 adolescent male rhesus macaques were trapped and held in single cages for 10 days. They were provided with one hour access to the same aspartame sweetened 8.4% ethanol solution that we use in the laboratory. The free-ranging rhesus macaques at Morgan Island (MI) drank considerably less than their captive counterparts at the Yemassee Primate Center (YPC?MI <.5 g/kg, YPC, 1.1 g/kg). This low level of consumption is most likely a function of the limited time that they have to learn the effects of alcohol and the novel setting in which they are exposed. As evidence of this, the subjects consume more in the second week than in the first. Age may also have influenced the comparison as a majority of Morgan Island males sampled to date have been adolescents and in the mainland Alpha Genesis laboratory facilities the young adults drank more per kg than the adolescents. At Morgan Island, adolescents and adults drank about the same limited amount of alcohol. However, since at MI we have few adult males (n=2) and they were elderly further data will be needed to confirm this preliminary finding. There has been considerable question concerning differences in alcohol intake between the primates at the Wake Forest laboratory and the nonhuman primates in the Intramural laboratory at Poolesville. The two laboratories use different species which differ considerably in temperament, with the cynomologus (used by Wake Forest) showing higher anxiety and the rhesus (used by the Intramural program) showing more impulsive and aggressive behavior. Hence species differences in alcohol intake between the two species would not be surprising. During this past year we were able to complete our comparison of these two nonhuman primate species (cynomologus and rhesus macaques) in alcohol intake. We found no differences between the two species in overall rates of intake using our one-hour access paradigm, although the female cynomologus macaques drank slightly more than both sexes of the two macaque species. The sample size for female cynomologus macaques was small, however, and needs to be replicated with more subjects. There have been numerous reports that squirrel monkeys will not consume alcohol and anecdotal reports that other New World species are reluctant to consume alcohol at appreciable quantities. Given the wide variety of different species at Alpha Genesis, we were able to show for the first time that a New World species (capuchins) will voluntarily consume alcohol to intoxicating levels. Alcohol intake for capuchins was comparable to that of the Old World species (cynomolgus and rhesus), with all three species drinking on average of about 1 gm/kg per hour, with some capuchin subjects drinking routinely at levels that would produce BAC in excess of 100 mg%. As in the rhesus macaques, among capuchins, males also drink more than female subjects. In a second series of studies with Stefan Tiefenbacher and Mark Laudenslager, we tested an interesting third macaque species, bonnet macaques to assess their voluntarily alcohol consumption patterns when provided a sweetened solution containing increasing concentrations of alcohol. This species is particularly interesting because they are easygoing and highly gregarious in temperament. Thus we would predict lower intake in this species. Four adult bonnet monkeys (2 males and 2 females) were tested for 60 minutes, four days a week. During the first two weeks an aspartame solution containing no alcohol (0%) was made available to train the subjects. Beginning on week 3, alcohol was added to the solution in increasing concentrations beginning at either 2 or 4% to increase the concentration to 6%. A jump in concentration from 0 to 4% resulted in a suppression of voluntary alcohol consumption. After a reduction to 2%, intake was maintained. By increasing the concentration from 0-6% in 2% steps, intake was not suppressed. Substantial inter-individual variability in mean alcohol intake at 6% was observed, with average intakes near .8 gm/kg per hour per day. Intake was variable, resulting in alcohol consumption between 0.53 and 0.92 gm/kg body weight. These data taken with those cited above suggest that when the solution is palatable and at concentrations are below 10% alcohol intake is a wide-spread proclivity between nonhuman primate species and that consumption patterns equivalent to the human pattern of two or three drinks per hour is the norm for the average subject, with wide individual variability within a species. Vasopressin and Oxytocin In one of the first studies to consider the relationship between OT and AVP, temperament and social behavior in free-ranging female rhesus macaques, CSF and blood samples were collected from non-lactating females and assayed for concentrations of OT and AVP. OT was correlated with growth hormone and the behavior "lay down without sleeping". AVP was correlated with the behavior "overall leaping". Results show no evidence for the strong relationship between oxytocin and social behavior that is seen in some highly social rodent species. The result for AVP is particularly interesting as our prior research show that long leaps between trees are an indicator of impulsivity and suggest that high levels of AVP are predictive of impulsive behavior. Rodent studies show that high AVP is related to increased alcohol intake. Research continues toward understanding the relationship between AVP, impulsivity and alcohol intake. SSRI Activity and Drug Response Fundamental questions remain regarding the actions of the selective serotonin reuptake inhibitors (SSRIs) on depression. To examine the time course of central and peripheral neurochemical effects of sertraline (SER) in non-human primates the second of a series of studies with George Anderson from Yale is reported. SER (20 mg/kg, p.o.) or placebo were administered daily for 4 weeks to two groups of six young adult male rhesus monkeys. Both groups received placebo during a 3-week baseline lead-in period and for 6 weeks after discontinuation. Blood and cisternal cerebrospinal fluid (cCSF) samples were obtained on days -21, -14, -7, 0, +3, +7, +14, +21, +28, +35 and +70. In animals receiving SER, mean (+/-SD) levels of cCSF serotonin (5-HT) increased from 38.6+/-9.0 pg/ml at baseline to 128+/-46.4 pg/ml during treatment (paired t=4.17, P=0.014). Concentrations of cCSF 5-HT were 290% of baseline on day 0 (+3 h), ranged from 260% to 436% of baseline during treatment, and returned to baseline 7 days after discontinuation. Levels of cCSF 5-hydroxyindoleacetic acid declined to 51+/-2.0% of baseline by day +3 and remained at similarly reduced levels during treatment. Plasma drug levels and decrements in platelet 5-HT were similar to those seen in patients. SER rapidly and substantially increases cCSF levels of 5-HT in primates, the extent of elevation is relatively constant during prolonged administration, and values return to baseline shortly after discontinuation. The results suggest that response latency for SSRIs in depression is not due to gradually increasing brain extracellular fluid 5-HT levels and tend not to support theories that posit SSRI response latency as being due to autoreceptor desensitization, transporter downregulation, or drug accumulation.